title: Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile.
abstract: OBJECTIVE
  RBx 11760, a novel oxazolidinone, was investigated for in vitro and in vivo activity against Clostridium difficile.
  
  
  METHODS
  The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 11760 on sporulation and toxin production was determined against different C. difficile isolates. We used a hamster infection model to investigate the efficacy of RBx 11760, vancomycin and metronidazole. The mechanism of action of RBx 11760 against C. difficile ATCC 43255 was determined by macromolecular synthesis inhibition.
  
  
  RESULTS
  RBx 11760 MICs were in the range of 0.5-1 mg/L for C. difficile isolates, and it demonstrated concentration-dependent killing of C. difficile ATCC 43255 and C. difficile 6387 up to 2-4× MIC (1-2 mg/L). RBx 11760, at concentrations as low as 0.25-0.5 mg/L, resulted in a significant reduction in de novo toxin production as well as sporulation in different C. difficile isolates. In contrast, vancomycin, metronidazole and linezolid had little or no effect on toxin production and appeared to promote the formation of spores. In the hamster infection model, treatment with RBx 11760 resulted in prolonged survival of animals as compared with vancomycin or metronidazole, which correlated well with the histopathology results. Macromolecular labelling results suggest that RBx 11760 is a potent inhibitor of bacterial protein synthesis.
  
  
  CONCLUSIONS
  RBx 11760 showed excellent in vitro and in vivo activity against C. difficile, and it could be a promising novel candidate for future drug development against C. difficile infection.
authors.affiliation: Department of Infectious Diseases, New Drug Discovery Research, Ranbaxy Research Laboratories, Gurgaon, Haryana, India. tarun.mathur.nz@dsin.co.in
authors.forename: Tarun
authors.initials: T
authors.lastname: Mathur
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.forename: Tarani K
authors.initials: TK
authors.lastname: Barman
authors.forename: G Ram
authors.initials: GR
authors.lastname: Kumar
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
authors.forename: Smita
authors.initials: S
authors.lastname: Singhal
authors.forename: V Samuel
authors.initials: VS
authors.lastname: Raj
authors.forename: Dilip J
authors.initials: DJ
authors.lastname: Upadhyay
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Bhatnagar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000096:biosynthesis; D016360:Clostridioides difficile / Q000187:drug effects* / Q000302:isolation & purification; D003015:Clostridium Infections / Q000188:drug therapy* / Q000382:microbiology; D006224:Cricetinae; D004195:Disease Models, Animal; D006801:Humans; D008647:Mesocricetus; D008795:Metronidazole / Q000008:administration & dosage; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000494:pharmacology*; D013171:Spores, Bacterial / Q000187:drug effects; D014640:Vancomycin / Q000008:administration & dosage
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D023303:Oxazolidinones; D008795:Metronidazole; D014640:Vancomycin